Search

Human neoplasias are often addicted to the cellular proteasome machinery. This has led to the development of bortezomib and carfilzomib proteasome inhibitors, approved for the treatment of multiple myeloma. Cancers, however, were found resistant to the proteasome inhibition in clinical trials, suggesting effective, cancer-specific compensatory responses. Here we employed global proteomics to determine contributions of compensatory mechanisms upon the proteasome inhibition with carfilzomib - in the cells of multiple myeloma, normal fibroblasts, and cancers of lung, colon, and pancreas. A pathway-oriented siRNA screen based on proteomics results showed that molecular chaperones, autophagy- and endocytosis-related proteins are cancer-specific vulnerabilities in combination with carfilzomib. HSP70 family chaperones HSPA1A/B were the most universal proteasome inhibition responders in the proteomes of all the studied cell types and HSPA1A/B inhibition most specifically sensitized cancer cells to carfilzomib in cell lines, patient-derived organoids and mouse xenografts. Overlap of proteomics with RNA-seq data showed that the proteasome inhibition-dependent HSPA1A/B induction in cancer cells is mainly transcription-driven and HSF1/2-dependent. Consequently, we found that a high level of HSPA1A/B mRNA is associated with a low proteasome activity in cancer patient tissues and is a risk factor in cancer patients with the low level of expression of the proteasome. Functionally, the HSPA1A/B induction does not affect a proteasome expression bounce-back upon the carfilzomib treatment, while it supports other mechanisms of the proteasome inhibition response - autophagy, unfolded protein response, and directly the 26S proteasome activity. We found that the 26S proteasome is chaperoned and protected from the inhibition with carfilzomib by HSPA1A/B assisted by DNAJB1 co-chaperone in cancer cells and using purified protein system in vitro. Thus, we define HSPA1A/B as a central player in the cellular compensatory response to the decreased proteasome activity, and the sensitive target in cancer cells with the inhibited proteasome.

Aim of the study To determine the correlation of protein serum levels of two cytokines and their polymorphisms, which have an influence on their expression. Material and methods The study group consisted of 65 patients (33 men, 31 women) who met the criteria for inclusion and exclusion of pancreatic cancer, and 41 patients (25 men, 16 women) with colorectal cancer. The control group consisted of 100 healthy volunteers (63 men, 37 women). Detection of polymorphisms was performed using TaqMan probes, and concentration of proteins by ELISA method. Results The mean TNF-α concentration in patients with colorectal cancer was significantly higher compared to the control group, p< 0.0001. A statistically significant difference was noted when comparing both study groups, p = 0.0009. The analyses show that the occurrence of the polymorphic genotype -308AA of the TNF-α gene was not correlated with the increased concentration of the examined protein in patients with both pancreatic and colorectal cancer. It was also noted that the concentration of TGF-β protein was significantly higher in patients with colorectal cancer than in patients with pancreatic cancer. These results also proved to be statistically significant, p = 0.0353. Conclusions The only statistically significant effects were the correlations between patients belonging to a specific group (pancreatic cancer/colorectal cancer/control) and average protein levels. There was no effect of sex or genotype on the occurrence of elevated levels of TNF-α and TGF-β protein control, despite their variability in particular types of cancer.

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition. This suggests a central role of HSP70 in the suppression of the proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced autophagy, unfolded protein response, and endocytic flux, and directly chaperones the proteasome machinery. However, it does not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of cancer cells with the inhibited proteasome and HSP70.

The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.

The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.

The presented recommendations concern the current management of acute pancreatitis. The recommendations relate to the diagnostics and treatment of early and late phases of acute pancreatitis and complications of the disease taking into consideration surgical and endoscopic methods. All the recommendations were subjected to voting by the members of the Working Group of the Polish Pancreatic Club, who evaluated them every single time on a five-point scale, where A means full acceptance, B means acceptance with a certain reservation, C means acceptance with a serious reservation, D means rejection with a certain reservation and E means full rejection. The results of the vote, together with commentary, are provided for each recommendation.

s / Pancreatology 15 (2015) S1eS141 S125 using the ECRHS (European Community Respiratory Health Survey) questionnaire that provides reliable diagnostic information about atopic disease and represents the largest case sample size examined for this association so far. Patients & methods: Detailed information about atopic diseases was reported for 1297 cases and 1024 controls in the PanGenEU Study. Associations between PDAC and asthma and nasal and skin allergies were studied through multilevel logistic regression. Meta-analysis using studies on the association between asthma and PDAC risk was performed applying random effects model. Results: Nasal allergies and related symptoms were associated with low risk of PDAC (OR 1⁄4 0.66, 95%CI 0.52e0.83 and OR 1⁄4 0.59, 95%CI 0.46e0.77, respectively). Skin allergies were not associated with PDAC risk (OR 1⁄4 0.95), but eczema symptoms presented within a year before patient recruitment showed an increased risk (OR 1⁄4 2.47, 95%CI 1.6e3.81). Asthma was associated with low PDAC risk (OR 1⁄4 0.64, 95% CI 0.47e0.88), in particular long-standing asthma (>17 years; OR 1⁄4 0.39, 95%CI 0.24e0.65). Meta-analysis of ten case-controls studies, including this study, showed significantly reduced PDAC risk among asthmatics (OR 1⁄4 0.73, 95%CI 0.59e0.89; P for heterogeneity 0.36). Conclusion: This study demonstrates a consistent inverse association between PDAC and nasal allergies and asthma, pointing to the involvement of immune and/or inflammatory factors in pancreatic carcinogenesis. Future studies will help to understand the mechanisms underlying these associations.